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A TRP channel trio mediates acute noxious heat sensing

Nature volume 555, pages 662666 (29 March 2018) | Download Citation

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Acute pain represents a crucial alarm signal to protect us from injury1. Whereas the nociceptive neurons that convey pain signals were described more than a century ago2, the molecular sensors that detect noxious thermal or mechanical insults have yet to be fully identified3,4,5,6. Here we show that acute noxious heat sensing in mice depends on a triad of transient receptor potential (TRP) ion channels: TRPM3, TRPV1, and TRPA1. We found that robust somatosensory heat responsiveness at the cellular and behavioural levels is observed only if at least one of these TRP channels is functional. However, combined genetic or pharmacological elimination of all three channels largely and selectively prevents heat responses in both isolated sensory neurons and rapidly firing C and Aδ sensory nerve fibres that innervate the skin. Strikingly, Trpv1−/−Trpm3−/−Trpa1−/− triple knockout (TKO) mice lack the acute withdrawal response to noxious heat that is necessary to avoid burn injury, while showing normal nociceptive responses to cold or mechanical stimuli and a preserved preference for moderate temperatures. These findings indicate that the initiation of the acute heat-evoked pain response in sensory nerve endings relies on three functionally redundant TRP channels, representing a fault-tolerant mechanism to avoid burn injury.

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  1. 1.

    Pain. Nature 535, S1 (2016)

  2. 2.

    The Integrative Action of the Nervous System (Oxford Univ. Press, 1906)

  3. 3.

    TRP channels and pain. Annu. Rev. Cell Dev. Biol. 29, 355–384 (2013)

  4. 4.

    ., & Peripheral thermosensation in mammals. Nat. Rev. Neurosci. 15, 573–589 (2014)

  5. 5.

    & How we feel: ion channel partnerships that detect mechanical inputs and give rise to touch and pain perception. Neuron 74, 609–619 (2012)

  6. 6.

    & Neural circuits for pain: recent advances and current views. Science 354, 578–584 (2016)

  7. 7.

    . et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–824 (1997)

  8. 8.

    ., & The cellular code for mammalian thermosensation. J. Neurosci. 33, 5533–5541 (2013)

  9. 9.

    ., & Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature 449, 607–610 (2007)

  10. 10.

    . et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288, 306–313 (2000)

  11. 11.

    . et al. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 405, 183–187 (2000)

  12. 12.

    ., ., ., & TRPV3 and TRPV4 ion channels are not major contributors to mouse heat sensation. Mol. Pain 7, 37 (2011)

  13. 13.

    . et al. TRP vanilloid 2 knock-out mice are susceptible to perinatal lethality but display normal thermal and mechanical nociception. J. Neurosci. 31, 11425–11436 (2011)

  14. 14.

    . et al. TRPM3 is a nociceptor channel involved in the detection of noxious heat. Neuron 70, 482–494 (2011)

  15. 15.

    . et al. The calcium-activated chloride channel anoctamin 1 acts as a heat sensor in nociceptive neurons. Nat. Neurosci. 15, 1015–1021 (2012)

  16. 16.

    . et al. Opening of an alternative ion permeation pathway in a nociceptor TRP channel. Nat. Chem. Biol. 10, 188–195 (2014)

  17. 17.

    . et al. Phenotyping sensory nerve endings in vitro in the mouse. Nat. Protocols 4, 174–196 (2009)

  18. 18.

    . et al. The capsaicin receptor TRPV1 is a crucial mediator of the noxious effects of mustard oil. Curr. Biol. 21, 316–321 (2011)

  19. 19.

    . et al. TRPA1 acts as a cold sensor in vitro and in vivo. Proc. Natl Acad. Sci. USA 106, 1273–1278 (2009)

  20. 20.

    . et al. Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nat. Neurosci. 18, 145–153 (2015)

  21. 21.

    & The TRPM2 ion channel is required for sensitivity to warmth. Nature 536, 460–463 (2016)

  22. 22.

    ., ., & Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress. J. Neurosci. 28, 2485–2494 (2008)

  23. 23.

    . et al. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112, 819–829 (2003)

  24. 24.

    . et al. Human TRPA1 is a heat sensor displaying intrinsic U-shaped thermosensitivity. Sci. Rep. 6, 28763 (2016)

  25. 25.

    . et al. Activation of planarian TRPA1 by reactive oxygen species reveals a conserved mechanism for animal nociception. Nat. Neurosci. 20, 1686–1693 (2017)

  26. 26.

    ., ., & . A simple and inexpensive method for determining cold sensitivity and adaptation in mice. J. Vis. Exp. (97): (2015). 10.3791/52640

  27. 27.

    ., ., ., & TRPV1-lineage neurons are required for thermal sensation. EMBO J. 30, 582–593 (2011)

  28. 28.

    & TRP channels in skin biology and pathophysiology. Pharmaceuticals (Basel) 9, e77 (2016)

  29. 29.

    . et al. The TRPM2 channel is a hypothalamic heat sensor that limits fever and can drive hypothermia. Science 353, 1393–1398 (2016)

  30. 30.

    . et al. Warm-sensitive neurons that control body temperature. Cell 167, 47–59.e15 (2016)

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We thank all members of the Laboratories of Ion Channel Research and Experimental Gynecology and Obstetrics for comments and discussion, and K. Luyten for assistance with histological and in situ staining. This work was supported by grants from the KU Leuven Research Council (PF-TRPLe and C1-TRPLe to Tho.V. and R.V.), the Research Foundation-Flanders (FWO G.084515N to J.V. and Tho.V. and G.099114N to Tho.V. and Thi.V.), the Queen Elisabeth Medical Foundation for Neurosciences (to Tho.V.), the Belgian Foundation Against Cancer (to J.V. and Tho.V.) and the Planckaert-De Waele fund (to J.V.). K.D.C. and K.H. are holders of a doctoral fellowship of the FWO Belgium.

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Author notes

    • Joris Vriens
    •  & Thomas Voets

    These authors jointly supervised this work.


  1. Laboratory of Ion Channel Research and TRP Research Platform Leuven (TRPLe), Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium

    • Ine Vandewauw
    • , Katrien De Clercq
    • , Marie Mulier
    • , Katharina Held
    • , Silvia Pinto
    • , Nele Van Ranst
    • , Andrei Segal
    • , Rudi Vennekens
    •  & Thomas Voets
  2. VIB Center for Brain & Disease Research, Leuven, Belgium

    • Ine Vandewauw
    • , Katrien De Clercq
    • , Marie Mulier
    • , Katharina Held
    • , Silvia Pinto
    • , Nele Van Ranst
    • , Andrei Segal
    • , Rudi Vennekens
    •  & Thomas Voets
  3. Laboratory of Experimental Gynecology and Obstetrics, Department of Development and Regeneration, University of Leuven, Leuven, Belgium

    • Katrien De Clercq
    • , Katharina Held
    •  & Joris Vriens
  4. Laboratory of Reproductive Genomics, Department of Human Genetics, University of Leuven, Leuven, Belgium

    • Thierry Voet
  5. Department of Anesthesiology, University of Erlangen-Nürnberg, Erlangen, Germany.

    • Katharina Zimmermann


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I.V., M.M. and J.V. performed cellular calcium imaging experiments. I.V. designed, performed and analysed all skin nerve recordings, with technical input and guidance from K.Z. and A.S. K.H., J.V. and Tho.V. performed patch-clamp experiments. I.V., K.D.C, K.H., S.P., M.M. and J.V. performed behavioural experiments. K.D.C. and N.V.R. performed histological analyses. I.V., Thi.V. and A.S. performed and analysed RNA-seq experiments. S.P. generated DKO and TKO mice, with supervision by R.V. I.V. and Tho.V. wrote the manuscript with input from all co-authors. J.V. and Tho.V. initiated and supervised the entire project.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Joris Vriens or Thomas Voets.

Reviewer Information Nature thanks J. Wood and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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  1. 1.

    Tail immersion assay of a WT and a TKO mouse.

    Video showing the tail immersion assay at 57 °C in a wild type and a TKO mouse.

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